The career goal of the K01 candidate is to become an independent investigator conducting research that contributes to the prevention of Alzheimer's disease (AD) dementia through elucidating disease mechanisms and deriving individual risk profiles during the preclinical stage of the disease. The environment at Massachusetts General Hospital and Harvard Medical School is ideal for the candidate's training and proposed research, providing state-of-the-art imaging facilities and a world-renowned community of AD researchers and clinicians. During this K award, the candidate will extend her expertise in multimodal neuroimaging by receiving training in Tau PET imaging, and acquire expertise in genetic analyses to pursue a novel research path. The research plan proposed herein examines the influence of known genetic risk factors, specifically the APOE4 genotype and 21 non-APOE loci associated with clinical AD in large GWAS analyses, on the relationship between AD biomarkers and cognitive decline in clinically normal older individuals (CN). An understanding of genetic risk factors within CN is especially relevant given the ability to select CN with biomarker evidence of elevated A? (preclinical AD). Although longitudinal studies have converged to reveal that CN with preclinical AD are at heightened risk of subsequent clinical impairment, heterogeneity in decline exists within this group, such that some of these individuals remain clinically normal for an extended period of time. Identification of genetic risk factors that influence the time between initial A? accumulation and the onset of clinical symptoms will greatly enhance our understanding of preclinical AD and improve our ability to identify individuals most at- risk for cognitive decline. Although some of the effects of known genetic risk factors for AD dementia are undoubtedly mediated by elevated A?, we hypothesize that these factors also influence the AD trajectory by interacting with A? to accelerate downstream effects such as the accumulation of neocortical Tau, neurodegeneration, and cognitive decline. Thus, for an equivalent level of A? burden, an individual with high genetic risk may show greater neurodegeneration than an individual with low genetic risk. This line of research should provide insight into why some A?+ individuals are able to remain clinically normal for longer periods of time whereas other A?+ individuals rapidly progress to clinical impairment. We will investigate these hypotheses in a large sample of 1777 CN combined across the Harvard Aging Brain Study (N=277), the Anti- Amyloid in Asymptomatic AD Study (A4, N=1000) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Study (LEARN, N=500). All CN will complete amyloid PET, structural MRI, genotyping data, and longitudinal neuropsychological testing, and a large subset will additionally complete Tau PET imaging (N=827). Because disease-modifying strategies are most likely to be successful during the preclinical stage, elucidating AD disease mechanisms and deriving individual risk profiles during the preclinical stage will have tremendous impact on the prevention of AD.